# Project-003

> **NIH NIH P01** · EMORY UNIVERSITY · 2024 · $401,314

## Abstract

ABSTRACT – Project 3
The overall objective of this Program project application is to generate a comprehensive understanding of the
complex host-pathogen interactions critical for HIV reservoir seeding and persistence such that novel cure
strategies truly targeted for the unique immune environment of children living with HIV (CLWH) can be created.
The knowledge gap we address in Project 3 is how the establishment and maintenance of HIV reservoirs are
regulated by the neonatal and childhood immune system, with specific focus on host and bacterial metabolites,
immunoregulatory cytokines, and thymic output. HIV persistence in adults is driven by recognizable
metabolomic and microbial profiles that include metabolites modulating epigenetic changes in genes regulating
innate/adaptive immune cell function and HIV latency. Studies in CLWH clearly demonstrate that the size of
the HIV reservoir is variable with a high dynamic range. The hypothesis to be tested in Project 3 is that age-
associated changes in HIV reservoir size and stability are driven by specific metabolites that influence CD4+
and CD8+ T cell function, cytokine production (e.g., IL-10 and TGF-β), and the level of HIV-infected recent
thymic emigrants (RTEs). In Aim 1, we will quantify the contribution of thymic output and infected RTEs to
changes in the size of the intact HIV reservoir. We will test the impact of the anti-inflammatory cytokine
environment prevalent in younger age groups on thymic output and HIV reservoir seeding. In Aim 2, we will
address how innate and adaptive cellular immune homeostasis and HIV-specific immune function are
influenced by the host environment and thymic output using high-dimensional flow cytometry, cytokine
analyses and transcriptional/epigenetic profiling on single cells. In Aim 3, we will decipher the impact of
microbial/host metabolites on production of IL-10 and TGF-β, establishment and maintenance of HIV
reservoirs, and innate/adaptive immune functions. Targeted metabolomics to quantify short chain fatty acids
and primary/secondary bile acids will be used to define and validate relationships with levels of intact and
translation competent HIV DNA. Finally, immunological, virological, and molecular data will be integrated, and
machine learning algorithms will be used to develop models to predict the magnitude and features of HIV
reservoirs. Longitudinal samples from two cohorts of CLWH (IMPAACT biorepository and EPIC4 study) allow
us to monitor dynamics of HIV reservoirs across childhood. A better understanding of the vulnerability of HIV
reservoirs to innate and adaptive immune pressure will drive informed approaches to a cure for CLWH. The
research proposed builds on our expertise with cutting-edge systems immunology to deeply interrogate HIV.
With multidisciplinary approaches, synergies across Projects and Cores, and our highly collaborative group of
established and early-stage investigators, we are confident that Project 3 will lead to important di...

## Key facts

- **NIH application ID:** 10814304
- **Project number:** 5P01HD112217-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ashish Arunkumar Sharma
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,314
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814304

## Citation

> US National Institutes of Health, RePORTER application 10814304, Project-003 (5P01HD112217-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814304. Licensed CC0.

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